Dr. Fors Connolly is a clinician at heart. 

The focus of the translational research in her group is underpinned by the patient focus. She explains, “my aim is to contribute to research that improves conditions for patients, by increasing awareness of complications following viral infections and identify which individuals are at risk of these complications, furthermore to identify new targets of treatment.”

In a nutshell, Dr. Fors Connolly and her team focus on acute and long-term complications following viral infections. Her research ranges from laboratory, clinical and population projects enabling a translational perspective from impact of molecules on infection to large-scale epidemiological studies. 

In the past two years, she has primarily focused on COVID-19, most recently driving a Nordic research collaboration to determine the clinical features and impact on organs of post-COVID-19 syndrome, the long-term effects of infection with SARS-CoV-2. This project, recently funded by the Swedish Research Council, utilizes clinical register data for more than 1.5 million COVID-19 patients, enabling the characterization of post-COVID syndrome. However, she has also performed research on Puumala Orthohantavirus that causes hemorrhagic fever with renal syndrome (HFRS) and plans to include influenza viruses in future research.

The molecular perspective: searching for the mechanism of glycocalyx degradation

When a person is infected with Puumala Orthohantavirus, they often develop the disease called hemorrhagic fever with renal syndrome (HFRS). HFRS increases the risk for heart attack, stroke and venous thromboembolism, especially in elderly patients. Dr. Fors Connolly is trying to figure out why and how by focusing on endothelial cells. 

With her collaborator, Dr. Marta Bally at the Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Dr. Fors Connolly is studying the inner surface of blood vessels to get at disease complications and be able to propose new therapeutic strategies. 

The response of endothelial cells to Puumala virus and SARS-CoV-2 infections may be key. She explains: 

We are interested in the endothelial cell response, and the part that is called the endothelial glycocalyx. The endothelial glycocalyx regulates the inflammatory response, thrombosis and vascular leakage and plays a role in pathogenesis in a multitude of other diseases such as coronary atherosclerosis, diabetes, sepsis and even other viral hemorrhagic fevers. 

From the molecular perspective:

In the most severe forms of HFRS, the level of endothelial glycocalyx degradation markers is increased. Therefore, our aim is to discern underlying molecular mechanisms of endothelial glycocalyx degradation and identify potential targets of intervention.

The glycocalyx of endothelial cells is a complex, mechanically protective layer made of proteoglycans, glycosaminoglycans, and plasma proteins. It is sensitive to all types of inflammation, protecting against leukocyte and platelet recruitment, helping with endothelial relaxation and preventing vascular leakage.

According to Dr. Fors Connolly, recent studies show that, “if you protect the glycocalyx, you likely also have protection against severe disease outcomes.”

Thanks to happenstance and a career entry into molecular virology, Dr. Chloé Jacquet, a postdoctoral fellow working with Dr. Fors Connolly is leading the hunt for the mechanism. Currently, she is homing in on the protein binding partners and functions of sheddases and matrix metalloproteinases (MMPs). Dr. Jacquet explains:

I’m setting up a model to try to determine which sheddase will degrade the glycocalyx. Depending on the outcome, we can look at sheddases to try to prevent the degradation. We are also going into a more complex system called Quartz Crystal Microbalance with Dissipation monitoring. With QCM-D, I will reproduce the barrier on a sensor made of quartz. I can then measure protein degradation using purified components or patient blood samples. 

The methods are complex, and Dr. Fors Connolly doesn’t waver in confidence, “Chloé is really a valuable asset, and I'm so grateful to have her in my lab. This lab research would not be possible without her.” 

The molecular mechanism studies are conducted in collaboration with Drs. Marta Bally and Fouzia Bano at WCMM in Umeå. 

The clinical perspective: looking for markers of patient vulnerability

Dr. Jacquet’s work in the lab links to the group’s clinical approach, searching for markers in elderly patients that assist with hospitalization decision-making. Working together with infectious disease clinicians that are recruiting SARS-CoV-2-, Puumala virus-, or influenza-infected patients to the infectious disease clinic at Umeå University Hospital, they will study the levels of endothelial glycocalyx degradation, asking: 

At a particular time-point, is the layer mostly degraded? What causes the degradation? Can we protect against it? Can we stop it? And, can we perhaps predict the outcome the individual will have following infection using samples obtained even before they were infected or the first sample at contact with the health care? 

explains Dr. Fors Connolly. From the practical perspective, this last question is one of the most important. Dr. Fors Connolly explains why: 

In Sweden, there's a shortage of hospital beds, even before the COVID-19 pandemic. In the emergency room, a clinician has to decide if a patient is bad enough to need hospitalization. I want to be able to contribute information that could help clinicians prioritize the most vulnerable patients. For example, this marker is high, so this patient should be hospitalized. 

The good news is that there are biomarker candidates that the team is following up on. They are extending the studies in collaboration with the Translational Vascular Research Group led by Dr. Lynn Butler at the University of the Arctic in Tromsø, Norway.  

Dr. Fors Connolly notes that collaborators are essential for the clinical work, “for example, with Prof. Clas Ahlm and Dr. Johan Normark in Umeå, responsible for HFRS and COVID-19 patient recruitment, we obtain plasma samples to look at endothelial glycocalyx degradation markers over time.” 

The epidemiological perspective: 1.5 million COVID-19 patients

The third layer of studies in the group comes from the widest perspective – population epidemiology. Dr. Fors Connolly explains: 

With registry data from the Swedish National Board of Health and Welfare, including the Swedish Intensive Care Registry, the Cause of Death Registry and Pharmaceutical Registry coupled with data from Statistics Sweden, the Public Health Agency Sweden, and the Swedish social insurance agency, Försäkringskassan, we can look deeply at >1 million COVID-19 patients.

With this data, there are socio-economic and clinical variables. The data are stored on a secure server, pseudonymized, and no personal identification numbers are available to the researchers.

And what can be done with that much data? Dr. Fors Connolly continues:

We can ask, what are the risk factors of severe disease outcome? Once you're infected, what's the risk of acute complications such as acute myocardial infarction and stroke? We recently had a paper published in The Lancet, demonstrating an increased risk for heart attack and stroke after COVID-19, and we currently have a new paper under review, where we've looked at the risk for blood clots.

This is not a project one embarks on alone, however. Dr. Fors Connolly reflects, “since I have a translational approach ranging over many topics, it is necessary to collaborate with people who have different areas of pre-clinical and clinical expertise to make it work.” 

Dr. Johan Normark, infectious disease doctor in Umeå and previous MIMS Clinical Research Fellow, is the investigator recruiting COVID-19 patients. Dr. Elin Thycell is part of the project at the Biobank Norr where samples are stored from before patients ever came in contact with the viruses. And, Dr. Fors Connolly points out that the dataset gets even stronger when national borders are removed: 

In a very interesting collaboration with Andrea Ganna and Hanna Ollila at the Institute for Molecular Medicine Finland, the Finnish node of the Nordic EMBL Partnership, as well as researchers at the University of Copenhagen, Denmark, we combine data to make a large Nordic COVID-19 cohort. We then use it to describe post-COVID-19 syndrome using diagnosis codes for affected organs, asking which organs are targeted during post COVID-19 syndrome, three months after they were diagnosed with COVID-19.

And, as she explains: 

It is a project that was actually made possible through Oliver Billker (MIMS Director), who set me in contact with Andrea Ganna. And then he put me in contact with Naja Hulvej Rod, who is a professor of epidemiology at Copenhagen University. Oliver Billker also helped identify our Norwegian collaboration partners, thereby we now have a truly Nordic post-COVID-19 perspective. 

With all the registry data available, even more research questions abound. With surgeon, Prof. Malin Sund, Dr. Fors Connolly determined that hormone replacement therapy protected against death due to COVID-19 (BMJ Open publication). On the flip-side, with Dr. Andrea Josefsson, a urologist and WCMM fellow, and MIMS Deputy Director Dr. Anna Överby Wernstedt, the team reported no effect of anti-testosterone treatment on COVID-19 outcome (European Urology publication).

Motivation for research and the future of the clinician-researcher

Taken together, Dr. Fors Connolly’s three-layer approach and work beautifully highlights what it takes to succeed in translational science - having an ambitious vision and high competence on all levels, from the molecular to the clinical and to population studies. She also has the right qualities to function as a spider in a web, connecting collaborators in different projects, making meaningful connections with a range of experts. 

For Drs. Fors Connolly and Jacquet, motivation comes from being close to the clinic and seeing the impact for patients. Dr. Jacquet explains, “during my PhD, most of my supervisors were clinicians, so I was always in close contact with the hospital; for me working on specific proteins at the cellular level, I need to know that the impact is meaningful.”

Dr. Fors Connolly agrees:

What drives me, I suppose, is that I'm a clinician at heart. I want to provide the best information and research for patients so that an elderly patient that comes into contact with healthcare can be treated as best as possible. For example, if there's a shortage of vaccines, then the most fragile individuals need to be prioritized for vaccination.That's my motivation.

Nearly all researchers can look back and identify mentors or role models who had an impact on their careers. For Dr. Fors Connolly, among her mentors is Prof. Clas Ahlm who recruited her to Umeå for a postdoc. She also fondly recalls the positive influence that Dr. Paddy Farrington, a statistician, had on encouraging her collaborative spirit. She explains:

Some years ago, I was supervising a medical student, and we had registry data and a question. Two weeks into the project, I realized that what we wanted to do was not possible! So, I sat down and just started trawling through the literature for possible solutions. And that's when I came across the self-controlled case series method. I just cold-sent an email to Paddy Farrington asking him for help. And he replied! It seemed like only moments later, we traveled to England to learn from Paddy and Heather Whitaker. 

Thanks to the openness of newly-established collaborators, that study produced an impactful publication in Circulation, identifying Puumala virus infection as a risk factor for heart attack or stroke. 

Dr. Fors Connolly is a role model for clinician-researchers. However, she is concerned about the future for clinician-researchers in Sweden: “research on all levels is important. It is a problem that we don't have more clinician-researchers. Most disease treatment guidelines, take COVID-19 most recently for example, are due to clinical research. So I'm very worried.”

She continues: 

In Sweden, there are structural fences, hindrances. When you are a clinician, it doesn't pay to be a researcher. You actually have a lower salary, and your clinical career is sidelined if you do choose to do research. Even high-level clinical managements don't prioritize research. They prioritize clinical production. I believe that there should be a requirement to do research. Not just medical doctors, but nurses and laboratory assistants should be able to be researchers.

This situation is one additional reason that Dr. Fors Connolly appreciates the MIMS Clinical Research Fellowship program. She notes that Läkarförbundet, the Swedish Medical Association, has had debate articles also highlighting this problem. She concludes, “it has consequences right now, and it has consequences for the future as well. Because what medical doctor would choose to do something that stops their clinical career and gives them a lower salary?”

The answer: Those that are driven by an internal passion for science. 

As a final message, Drs. Fors Connolly and Jacquet both remind us of the importance of humility in our daily scientific work and to embrace internal passion for science with a motto that encapsulates curiosity:

The more you know, the more you don't know. 

Brief career summary

Dr. Anne-Marie Fors Connolly was initially trained in the prestigious Human Biology program at the University of Copenhagen, Faculty of Health Sciences completing the M.Sc. degree in 2006, entering the field of virology with studies of the Crimean-Congo Hemorrhagic Fever virus during the time. At Karolinska Institutet she was awarded KID-funding to work on the Crimean-Congo Hemorrhagic Fever virus and completed her PhD degree in Medical Sciences, Infection Biology in 2010. Postdoctoral research coincided with formal medical training at Umeå University (MD degree in 2018). She is currently a group leader and medical resident in Clinical Microbiology at Umeå University Hospital. Since spring 2020, Dr. Fors Connolly has been a MIMS Clinical Research Fellow. She was recently awarded a total of 3 million SEK from the Swedish Research Council for a Nordic collaborative study on post-COVID-19 syndrome, and 3.9 million SEK from Kempe Foundation and Central and Base-unit ALF funding for studies to predict severe disease outcome using patient samples and biobank samples.  

The article is published as part of the “Behind the Science'' profile series, taking an in-depth look at a scientist or group within the Nordic EMBL Partnership.

CONTACT

Anne-Marie Fors Connolly
MIMS Clinical Research Fellow, resident in Clinical Microbiology
anne-marie.fors.connolly@umu.se